Uses for medical devices having a lubricious, nitric oxide-releasing coating

ABSTRACT

Methods are provided for delivering nitric oxide to the vascular tissue of a patient to inhibit or prevent restenosis or improve vascular function following various surgical procedures or associated with various NO-related conditions. The disclosed methods comprise contacting the vascular tissue of a patient with a medical device coated with a coating comprising nitric oxide associated with and releaseable from a polyurea network formed from the reaction on said medical device of a polyisocyanate; an amine donor and/or hydroxyl donor; an isocyanatosilane adduct having terminal isocyanate groups and at least one hydrolyzable alkoxy group bonded to silicon; and optionally a polymer selected from the group consisting of polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and polyacrylic acid.

[0001] This application is a continuation-in-part of U.S. applicationSer. No. 09/405,024, filed Sep. 27, 1999, which is acontinuation-in-part of U.S. application Ser. No. 09/163,038, filed Sep.29, 1998, which applications are herein incorporated by reference intheir entirety.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates generally to the uses for a drug-coatingcomplex which is drug-releasing in physiological media. Moreparticularly, the invention relates to methods of using medical devicescoated with a lubricious, nitric oxide-releasing coating for thetreatment of vascular disorders, including restenosis, and the inductionof angiogenesis.

[0004] 2. Related Art

[0005] It has long been known that hydrophilic coatings with lowfriction (coefficient of friction of 0.3 or less) are useful for avariety of medical devices such as catheters, catheter introducers andthe like. When low friction surfaces are used, the devices, uponintroduction into the body, slide easily within arteries, veins andother body orifices and passageways. There have been a wide variety ofmethods used to provide the surfaces desired. In some cases the materialof the catheter or medical device is formed of a material having goodanti-friction properties such as poly(tetrafluoroethylene) or otherplastics which tend to avoid abrasion with the body. However, in manycases the selection of materials does not provide the anti-slipproperties desired in conjunction with other desirable properties forthe particular medical device.

[0006] Prior art hydrophilic coatings typically rely on a two step, twocoating process, usually involving a primer coat of isocyanate orisocyanate/polymer blend which is dried, followed by a second coatcontaining at least one hydrophilic polymer such as polyvinylpyrrolidone or polyethylene oxide. The two coatings, one superimposed onthe other, are then baked to effect a cure. This forms an interpolymercomplex or a network including the hydrophilic polymer. Severaldisadvantages to this process exist.

[0007] First, the exact ratio of primer material to the hydrophilicpolymer is difficult to control, as it depends on whatever amounts ofprimer and hydrophilic polymer happen to be deposited by the wet filmduring the respective coating steps. Second, the primer may begin toredissolve in the second coating solution, causing some loss of primerand further resulting in difficulty in controlling theprimer/hydrophilic polymer ratio. Third, the hydrophilic polymer is notcovalently bonded to the substrate and may bond to other materials inthe area leading the coating to lose its desired properties. Fourth,additional facilities and time are needed for coating with a two stepprocess, as compared to a one step process.

[0008] Prior patents have suggested applying solutions ofpolyvinylpyrrolidone with isocyanate and/or polyurethane in multi-stepoperations. These coatings often lack good durability. For example, U.S.Pat. No. 4,585,666 issued to Lambert discloses medical devices havinghydrophilic coatings formed from an isocyanate layer overcoated with apolyvinylpyrrolidone layer. However, the multistep procedure makes itdifficult to tailor the properties and values of the final coatings.

[0009] U.S. Pat. No. 4,625,012, Rizk et al., describes a one step methodfor preparing moisture curable polyurethane polymers having pendantalkoxysilane groups and isocyanate terminals on a substrate. The methodincludes reacting an isocyanatosilane adduct and an isocyanate differentfrom the isocyanatosilane with a polyol. The isocyanatosilane adduct andthe isocyanate have at least two isocyanato groups each. Furthermore,the isocyanatosilane is produced by reacting an isocyanate having atleast three isocyanato groups with an organofunctional alkoxysilane. Thecoating formed, however, is not lubricious.

[0010] In U.S. Pat. No. 4,373,009, Winn, a coating process for preparinga lubricious coating is disclosed. A coupling agent is first applied tothe substrate. A coating is then applied on top of the coupling agent.The coupling agent bonds the coating to the substrate. Although thecoupling agent and coating may be applied to the substrate from the samesolution, the preferred method is to apply them separately.

[0011] U.S. Pat. No. 5,645,931, Fan et al., describes a one step coatingprocess for preparing a thromboresistant lubricious coating. The coatingis comprised of a substantially homogeneous composite of polyethyleneoxide and polyisocyanate in an inert solvent. However, the one stepcoating process is only suitable for polymeric substrates.

[0012] U.S. Pat. No. 5,662,960, Hostettler et al., describes a processfor producing slippery, tenaciously adhering hydrogel coatingscontaining a polyurethane-polyurea (PU/PUR) hydrogel commingled with apoly(N-vinyl pyrolidone) hydrogel. The coating may be applied onplastic, rubber, or metallic substrates. However, the process isperformed in several steps. Initially, plastic substrates are activatedby oxidative chemical treatments and plasma treatments with oxygen ornitrogen containing plasma gases. Metallic substrates are treated withaminosilane primers. Then, a base coat of PU/PUR hydrogel is applied tothe substrate followed by the application of a coat of a secondhydrogel.

[0013] Exposure to a medical device which is implanted or inserted intothe body of a patient can cause the body tissue to exhibit adversephysiological reactions. For instance, the insertion or implantation ofcertain catheters or stents can lead to the formation of emboli or clotsin blood vessels. Similarly, the implantation of urinary catheters cancause infections, particularly in the urinary tract. Other adversereactions to medical devices include inflammation and cell proliferationwhich can lead to hyperplasia, occlusion of blood vessels, plateletaggregation, rejection of artificial organs, and calcification.

[0014] To counter the adverse reactions which often accompany a medicalimplant or insert, pharmaceutically-active agents have been applied toor embedded within medical devices by covering the surface with acoating containing the active agent. Accordingly, medical devicecoatings are known which release a pharmaceutically-active agent viadissolution of the active agent or by cleavage of the active agent fromthe coating. Other drug-releasing coatings operate by hydrolyzing orotherwise cleaving a coating-active agent bond.

[0015] One approach to the incorporation of a pharmaceutically activeagent into a polymeric network is to absorb the active agent into thecoating from a solution. Hydrophilic polymers in contact with an aqueoussolution of an active agent, such as by soaking the polymer in asolution of the active agent, will swell to contain the solution andabsorb the active agent dissolved therein. Upon drying, the polymericnetwork includes the associated active agent. The use of such apolymeric network as a coating for a medical device allows for theassociation and immobilization of a water soluble active agent withand/or within the medical device. The active agent can then be releasedfrom the coating upon contact with aqueous body fluids.

[0016] Another approach to the association of a pharmaceutically-activeagent with a polymeric coating is by chemical attachment, e.g., covalentattachment, of the active agent to the coating. For example, coatingcompositions are known which include a nitric oxide-releasing functionalgroup bound to a polymer. U.S. Pat. Nos. 5,676,963 and 5,525,357disclose such polymeric coating compositions.

[0017] Nitric oxide (NO), has been implicated in a variety ofbioregulatory processes, including normal physiological control of bloodpressure, macrophage-induced cytostasis and cytotoxicity, andneurotransmission. NO inhibits the aggregation of platelets. NO alsoreduces smooth muscle cell proliferation thereby reducing restenosis.Consequently, NO can be used to prevent and/or treat complications suchas restenosis and thrombus formation when delivered to treatment sitesinside an individual that have come in contact with medical devices.

[0018] Several hypotheses regarding the mechanism of action of NO invarious processes have been put forward but none has yet been provenconclusively. These hypotheses include such disparate ideas as 1) NO maystop cellular proliferation and induce a program of differentiation(Babaei et al. Circ. Res. 82:1007-1015 (1998)) and/or 2) that there aredual signals required for NO to be active, e.g. that NO induces scalarmotion in cells but that a second signal, possibly provided by a growthfactor, is needed to indicate the direction in which motion will occur(Noiri et al. Am. J. Physiol. 274:C236-C244 (1998)). Other investigatorshave reported that ribonucleotide reductase is inhibited by NO,explaining the cell-cycle specific effect of NO in inhibiting vascularsmooth muscle cell proliferation (Sarkar et al. J. Hypertens. 15:275-283(1997)). Because NO is such a potent, multifaceted biological responsemodifier, the challenge in the development of NO-based pharmaceuticalsis to deliver an effective amount locally.

[0019] Restenosis limits the successful outcome of percutaneousprocedures used to recanalize atherosclerotic coronary arteries.Ischemic heart disease caused by atherosclerotic lesions of coronaryarteries underlies about 500,000 to 600,000 deaths per year (Bierman, E.L., Atherosclerosis and Other Forms of Arteriosclerosis in Principles ofInternal Medicine, Braunwald, E. et al. Eds., McGraw-Hill, New York,(1987)). Current surgical therapies used to circumvent these lesionsinclude coronary artery bypass graft surgery (CABG) and less invasiveprocedures such as percutaneous translumenal coronary angioplasty (PTCA)or atherectomy. PTCA is performed in approximately 400,000 US patientsand 650,000 patients world-wide (Lemaitre et al AngioplastyIndustry—Slower Growth on Tap as Balloon Prices Deflate, Cowen-IndustryStrategies, Cowen & Co., 1-70 (1994)). The major problem associated withPTCA is the occurrence of restenosis (late arterial narrowing) whichoccurs in about 30-40 percent of all patients undergoing PTCA(Blackshear et al. J. Am. Coll. Cardiol. 9:834-848 (1987)) within 3-6months.

[0020] The pathophysiology of restenosis is complex but localized.Injury to the arterial wall during angioplasty is the initiating eventcausing restenosis, but progression and severity are influenced byextent of vascular injury and platelet aggregation, individual anatomicand hemodynamic conditions, disruption of the endothelial lining andstimulation of vascular smooth muscle cell proliferation, migration, andextracellular matrix secretion (Bauters et al. Cardiovasc. Res.31:835-846 (1996); Landzberg et al. Progr. Cardiovasc. DiseasesXXXIX:361-398 (1997)).

[0021] Improved therapies for restenosis are needed. Only a small numberof therapies are currently approved for human use. Surgical approachesin addition to repeat angioplasty include CABG or the less invasiveprocedure of directional atherectomy. These procedures are moreexpensive, more traumatic, and therefore less preferred except inunusual circumstances. The only FDA-approved pharmacologic agent for useafter balloon angioplasty is administration of the potent anti-plateletagent, GPIIb/IIIa antibody (c7E3), which inhibits thrombus formation andacute reclosure, and has recently been reported to reduce clinicalrestenosis by 20-30 percent at six month follow-up (Gottsauner-Wolf etal. Clin. Cardiol. (USA) 19:347-356 (1996)). However, its utilityremains limited by the fact that (i) it is administered systemicallyand, unless heparin dose is carefully controlled, it can lead tobleeding complications; (ii) it is only effective in 20-30 percent ofcases; and (iii) its high price has limited its widespread use for allangioplasty patients (Holmes, D. R. N. Engl. J. Med. 336:1748-1749(1997)).

[0022] Mechanical approaches, used in ca. 25 percent of angioplastyprocedures performed in 1995, include two types of FDA-approvedintracoronary stents, the Gianturco-Roubin Flex-Stent (Cook Cardiology)and the Palmaz-Schatz stent (Johnson & Johnson). Recently, two othercoronary stents were approved for use in the U.S., the Medtronic/AVE XTStent, with its unique “rib-cage” design, and Bard's MEMOTHERM®, aNitinol self-expanding stent, is now used throughout the world. Stentsare endovascular metal alloy scaffoldings of 10-20 mm in length, which,when inserted after angioplasty, produce an initially larger coronarylumen and prevent vessel recoil. Stents limit the long-term build-up ofplaque and scar tissue, reducing clinical restenosis by 20-30% after 6months, but are still subject to late reclosure due to smooth musclecell overgrowth and thrombus formation (Bauters et al. Cardiovasc. Res.31:835-846 (1996); Gottsauner-Wolf et al. Clin. Cardiol. (USA)19:347-356 (1996)).

[0023] Loss of endothelial NO after arterial injury may contribute torestenosis. NO is one of at least three locally vasoactive systems, theother two being angiotensin II and bradykinin (Gibbons, S. H. Clin.Cardiol. 20(Supp2):II-II1 1835 (1997)). Under basal conditions, NOmodulates vascular tone, serves as an antithrombotic agent, and inhibitsvascular smooth muscle cell proliferation. Deficiency of this criticalbiological modifier may contribute to a variety of vascular disorders,including hypertension, atherosclerosis and restenosis (Myers et al.Int. J. Cardiol. 55:183-191 (1996)). Replacement of this endogenouslevel of NO may prove therapeutic for these conditions. Unfortunately,short therapeutic half-life, drug tolerance and systemic absorption withpotentially adverse hemodynamic effects limit the use of conventionalnitrate preparations.

[0024] Myocardial ischemia (reduction in blood flow and/or oxygensupply) occurs in a variety of clinically important settings, rangingfrom coronary artery disease and stable angina to myocardial infarction.The present invention addresses these problems by restoring the heart'sblood supply. In the case of vessel blockage, successful removal of thatblockage may be reversed by restenosis. Prevention of restenosis isessential.

[0025] Replacement of NO reduces restenosis. Other methods of NOreplacement have been tried such as gene therapy; in fact, directtransfer of a cDNA encoding endothelial NO synthase has been shown toinhibit neointimal lesion formation and improve vascular reactivity (vonder Leyden et al. Semin. Interv. Cardiol. 1:209-214 (1996)). Althoughexciting, such gene transfers are costly and relatively inefficient.Creation of a local depot of an NO-generating agent capable of sustainedNO release is an attractive alternative.

[0026] Of interest are the NCI group's studies on the effect of NOrelease rate on the growth of vascular smooth muscle cells in vitro(Mooradian et al. J. Cardiovascular Pharmacol. 25:674-678 (1995)). ThreeN-nitroso compounds with radically different half lives were evaluated:SPER/NO (t_(½) of 39 minutes); DPTA/NO (t_(½) of 3 h) and DETA/NO (t_(½)of 20 h). An inverse relationship was found between the IC₅₀ values andthe half lives, suggesting that this type of NO donor would also proveto be useful inhibitors of intimal hyperplasia and restenosis aftervascular injury.

[0027] Induced angiogenesis can be therapeutic and may be mediated byNO. Therapeutic angiogenesis results from the induction of new bloodvessel development in areas with limited blood flow (Engler, D. A.,Circulation 94:1496-1498 (1996); Simons, M. and Ware, J. A., Nature Med.2:519-520 (1996)). Isner's group (Murohara et al., J. Clin. Invest.101:2567-2578 (1988)) tested the hypothesis that endothelial NOsynthase, and thus NO, modulates angiogenesis in rabbits and mice withoperatively induced hindlimb ischemia and concluded that NO synthasemodulates angiogenesis in response to tissue ischemia.

[0028] NO can stimulate angiogenesis in combination with transmyocardiallaser revascularization. Transmyocardial laser revascularizationimproves heart function and quality of life in patients with refractorycoronary ischemic syndromes (Mirhoseini et al., Ann. Thorac. Surg.45:415-420 (1988); Donovan et al., Am. Coll. Cardiol. 30:607-612 (1997);Horvath et al., J. Thorac. Cardiovasc. Surg. 113:645-653 (1997); Cooleyet al., J. Thorac. Cardiovasc. Surg. 111:791-797 (1996); Horvath et al.,J. Thorac. Cardiovasc. Surg. 111:1047-1053 (1996)). The mechanism oflaser revascularization does not depend on long term patency ofmyocardial channels but more likely stimulation of angiogenesis(Yamamoto et al., J. Am. Coll. Cardiol. 31:1426 (1998); Gassler et al.,Circulation 95:371-375 (1997); Kohmoto et al., Ann. Thorac. Surg.61(3):861-868 (1996); Burkhoff et al., Ann. Thorac. Surg.61(5):1532-1534 (1996)). Approaches to increase regional blood flow viadirect delivery of angiogenic factors or their cognate genes have alsodemonstrated promise and numerous clinical trials have begun(Yanagisawa-Miwa et al., Science 257:1401-1403 (1992); Giordano et al.,Nat. Med. 2:534-539 (1996); Mack et al., J. Thorac. Cardiovasc. Surg.115:168-176 (1998); Baumgartner et al., Circulation 97:1114-1123 (1998);Lazarous et al., Circulation 94:1074-1082 (1996); Schumacher et al.,Circulation 97:645-650 (1998); Laham et al., J. Am. Col. Cardiol.31(supp. A):394A (1998); Henry et al., J. Am. Col. Cardiol. 31(supp.A):65A (1998)).

[0029] The best characterized angiogenic factors, VEGF and bFGF, arealso NO-dependent vasodilators (Horowitz et al, Arterioscler Thromb.Vasc. Biol. 17:2793-2800 (1997)). Myocardial ischemia upregulates VEGF,its receptors and NO release (Kitakaze et al., J. Mol. Cell. Cardiol.27:2149-2154 (1995); Node et al., Circulation 93:356-364 (1996)) andblocking endogenous NO production inhibits VEGF induced angiogenesis(Ziche et al., J. Clin. Invest. 99:2625-2634 (1997), Hood et al., Am. J.Physiol 274:H1054-H1058 (1998)). Myocardial implant devices stimulateangiogenesis and provide a logical platform for delivering therapeuticfactors to augment the heart's angiogenic response. NO is a potentvasodilator and mediator of angiogenesis. An NO-generating implantdevice would therefore be expected to represent a safer, moreefficacious and less costly approach for treating patients withrefractory coronary ischemic syndromes' (so-called “no option” patients)and mediating the induction of angiogenesis.

[0030] The systemic benefits of NO treatment are known. Inhaled NO is amodulator of distal pulmonary tone in endotoxin-induced pulmonaryhypertension (Lambermont et al, Crit. Care Med. 27(9):1953-1957 (1999)),implicating NO as an agent for improving pulmonary circulation. Theeffects of NO inhalation on pulmonary hypertension and blood flow hasbeen demonstrated in combination with other hemodynamic agents(prostacyclin, Max et al., Intensive Care Med. 25(10):1147-1154 (1999));and (almitrine, Paven et al., Anesthesiology 89(5):1157-1165 (1998)).

[0031] Other recognized or implicated systemic benefits of NO therapyinclude: the treatment of benign prostatic hyperplasia (Gradini et al.,J. Pathol. 189(2):224-229 (1999)); the regulation of amniotic fluid(El-Haddad et al., Am. J. Physiol. 277 (4 Pt2):R981-R986 (1999)); thestimulation of olfactory associative learning (Samama et al., Neurobiol.Learn. Mem. 71(2):219-231 (1999)); the correction of hypoxemiaassociated with Eisenmenger syndrome (Goodwin et al., Am. J. Obstet.Gynecol. 180(1 Pt 1):64-67 (1999)); the prevention of the impairment ofleft ventricle contractility after endotoxemia (Ishihara et al., J.Appl. Physiol. 85(6):2018-2024 (1998)); the treatment ofventilation/perfusion mismatch and pulmonary hypertension associatedwith acute respiratory distress syndrome (Jacobs et al., Am. J. Respir.Crit. Care Med. 158(5 Pt 1):1536-1542 (1998)); the mediation of sensoryinhibition (Adams et al., J. Pharmacol. Exp. Ther. 287(2):760-765(1998)); the control of Mycobacterium tuberculosis during primarypulmonary infection (Cooper et al., Infect. Immun. 68(3):1231-1234(2000)); the treatment of acute chest syndrome of sickle cell disease(Sullivan et al., Crit. Care Med. 27(11):2563-2568 (1999)); thetreatment of Raynard's phenomenon in scleroderma patients (Freedman etal., Lancet 354(9180):739 (1999)); the improvement of cardiac functionafter heart transplantation (Carrier et al., J. Heart Lung Transplant18(7):664-667 (1999)); the maintenance of cerebrovascular tone and thereversal of cerebral vasospasms (Kiris et al., Acta Neurochir (Wien)141(12):1323-1328, 1328-1329 (1999)); the improvement of pulmonary andsystemic circulation after endothelial induced bronchoconstriction(Lewis et al., Br. J. Pharmacol. 126(1):93-102 (1999); the reduction ofchest tube drainage and decrease of pulmonary artery pressure(Berkenbosch et al., Crit. Care Med. 27(5):1022-1024 (1999)); and thecontrol of pulmonary artery pressure, the improvement in arterialoxygenation efficiency and the prevention of epethelial apoptosis(Holopainen et al., Acta Paediatr. 88(10):1147-1155 (1999)).

[0032] Nitric oxide appears to also play a primary role in thedevelopment of an erection and the controllable and predictable releaseof NO to the penis by a catheter or other delivery means coated with ormade of a NO-releasing polymer is described in U.S. Pat. No. 5,910,316.

[0033] Because nitric oxide, in its pure form, is a highly reactive gashaving limited solubility in aqueous media, it is difficult to introducein a reliable and controllable form. NO is too reactive to be usedwithout some means of stabilizing the molecule until it reaches thetreatment site. Thus, NO is generally delivered to treatment sites in anindividual by means of polymers and small molecules which release NO.

[0034] In mammalian cells, NO arises through the action of a family ofNO synthases which catalyze the oxidation of one of the two guanidinonitrogens in L-arginine. NO is made by a variety of cells includingvascular endothelial cells and platelets. Because it is a potentbiological regulator, NO also can induce cell killing and/orhypotension. For this reason its administration must be closelycontrolled. Implant devices made from materials coupled to NO-generatingagents should address the need to deliver an effective amount of NOlocally without the introduction of toxic, free radical effects.

[0035] Different approaches to providing pharmacologically active NOhave been tried. It is known that long-term oral administration of theNO precursor, L-arginine, enhances NO production and reduces restenosis(McNamara et al. BBRC 193:291-296 (1993)). Local intramural delivery ofL-arginine is also effective in rabbits (Schwarzacher et al. Circulation95:1863-1869 (1997)), restoring endothelium-dependent vasodilation andenhancing local NO production. Chronic inhalation of NO inhibitsneointimal formation in the rat (Lee et al. Circ. Res. 78:337-342(1996)) but would be difficult clinically. Interestingly, treatment of700 stable coronary patients by local infusion of the NO-donorlinsidomine followed by oral molsidomine (another NO-donor) over a 6month period was associated with only a modest improvement in thelong-term angiographic result but had no effect on clinical outcome (theACCORD study; Lablanche et al. Circulation 7:83-89 (1997)), supportingthe idea that NO is best given locally at higher concentrations than arepossible systemically because of the multitude of potential side effectsof systemic administration. Support for this method of administrationhas been provided by Loscalzo's group (Marks et al. J. Clin. Invest.96:2630-2638 (1995)) who demonstrated inhibition of neointimalproliferation in rabbits after vascular injury by a single localtreatment with S-nitroso serum albumin, a naturally occurring adduct ofNO. Stents coated with this protein also significantly reducerestenosis.

[0036] The present invention is directed to overcoming the shortcomingsof current NO therapy by combining the benefits of a lubricious coatingwith the therapeutic and prophylactic benefits associated with anNO-releasing coating, and using such coated medical devices to treatvascular conditions, including restenosis, and induce angiogenesis.

SUMMARY OF THE INVENTION

[0037] One aspect of the present invention is directed to a coatedsubstrate comprising (a) a substrate; and (b) a polyurea and/orpolyurethane network capable of accommodating a pharmaceutically-activeagent, said polyurea and/or polyurethane network formed from thereaction, on at least a portion of the surface of said substrate to becoated, of a mixture comprising a polyisocyanate; an amine donor and/ora hydroxyl donor; an isocyanatosilane adduct having at least oneterminal isocyanate group and at least one hydrolyzable alkoxy groupbonded to silicon; and optionally a polymer selected from the groupconsisting of polyethylene oxide, polyvinyl pyrrolidone, polyvinylalcohol, polyethylene glycol, and polyacrylic acid.

[0038] It is a further aspect of the present invention to provide anarticle comprising a substrate on which a coating is formed comprising apolyurea and/or polyurethane network capable of accommodating apharmaceutically-active agent, formed from the reaction, on a substrateto be coated, of a mixture comprising a polyisocyanate; an amine donorand/or a hydroxyl donor; an isocyanatosilane adduct having terminalisocyanate groups and at least one hydrolyzable alkoxy group bonded tosilicon; and optionally, a polymer selected from the group consisting ofpolyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol,polyethylene glycol, and polyacrylic acid; in a solvent.

[0039] It is a further aspect of the present invention to provide adrug-releasing coating comprising an active agent associated with andreleaseable from a polymeric network formed from the reaction, on asubstrate to be coated, of a mixture comprising a polyisocyanate; anamine donor; and an isocyanatosilane adduct having terminal isocyanategroups and at least one hydrolyzable alkoxy group bonded to silicon; andoptionally, a hydroxyl donor and/or a polymer selected from the groupconsisting of polyethylene oxide, polyvinyl pyrrolidone, polyvinylalcohol, polyethylene glycol, and polyacrylic acid; in a solvent.

[0040] According to yet another aspect of the present invention, amethod is provided of preparing a lubricious coating on a substrate tobe coated comprising: forming a mixture of a polyisocyanate, an aminedonor and/or a hydroxyl donor; a polymer selected from the groupconsisting of polyethylene oxide, polyvinyl pyrrolidone, polyvinylalcohol, polyethylene glycol, and polyacrylic acid; and anisocyanatosilane adduct having terminal isocyanate groups and at leastone hydrolyzable alkoxy group bonded to silicon, in a solvent; applyingthe mixture to the substrate; and curing the mixture on the substrate toform the coating.

[0041] A further aspect of the present invention is to provide a methodof preparing a nitric oxide-releasing coating on a substrate to becoated, comprising: forming a mixture of a polyisocyanate, an aminedonor, an isocyanatosilane adduct having terminal isocyanate groups andat least one hydrolyzable alkoxy group bonded to silicon, and optionallya hydroxyl donor and/or a polymer selected from the group consisting ofpolyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol,polyethylene glycol, and polyacrylic acid, in a solvent; applying themixture to the substrate; contacting the coated substrate with a nitricoxide-releasing agent; and curing the mixture on the substrate to formthe coating.

[0042] It is a further aspect of the present invention to provide anitric oxide-releasing coated article or medical device produced by orproduceable by the coating method of the present invention.

[0043] It is a further aspect of the present invention to providemethods of delivering a therapeutic dose of nitric oxide in a patient inneed thereof by contacting the vascular tissue of a patient with amedical device coated with a lubricious, nitric oxide-releasing coatingof the invention.

[0044] These and other features and objects of the invention are morefully appreciated from the following detailed description of preferredembodiments of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] According to the present invention, a lubricious coating isformed by the reaction, on a substrate to be coated, of a mixturecomprising a polyisocyanate; an amine donor and/or a hydroxyl donor; anisocyanatosilane adduct having terminal isocyanate groups and at leastone hydrolyzable alkoxy group bonded to silicon; and a polymer selectedfrom the group consisting of polyethylene oxide, polyvinyl pyrrolidone,polyvinyl alcohol, polyethylene glycol, and polyacrylic acid; in asolvent. The resulting coating is drug-accommodating and, when theoptional hydrophilic polymer is incorporated into the mixture, becomeshighly lubricious.

[0046] It is believed that the isocyanate functional groups of thepolyisocyanate and isocyanatosilane react with the amine donor to form apolyurea network or with the hydroxyl donor to form a polyurethanenetwork. Furthermore, the silane groups of the isocyanatosilane arebelieved to form covalent bonds with the substrate to which the coatingis applied when cured in the presence of moisture to form a stronglyadherent coating.

[0047] The coating mixture is prepared in solution by weighing theappropriate quantities of polyisocyanate; amine donor and/or hydroxyldonor; isocyanatosilane adduct; and a polymer selected from the groupconsisting of polyethylene oxide, polyvinyl pyrrolidone, polyvinylalcohol, polyethylene glycol, and polyacrylic acid; and adding them intoan appropriate mixing vessel. Additional solvents may be added to adjustthe viscosity of the mixture. The choice of ingredients in the coatingmixture also affects the physical properties of the overall coating.Solids contents in a range of from about 0.2 to about 2.5% arepreferred. This solution is mixed well and then applied to anappropriate substrate such as catheter tubes, medical tubingintroducers, polymer coated medical wires, stents, dilatation balloons,implants, prostheses, and penile inserts, by conventional coatingapplication methods. Such methods include, but are not limited to,dipping, spraying, wiping, painting, solvent swelling, and the like.

[0048] The materials of construction of a suitable substrate include,but are not limited to, polymers, metal, glass, ceramics, composites,and multilayer laminates of the aforementioned materials.

[0049] The coatings of the present invention are drug-accommodating. Asused herein, the term “drug accommodating” refers to the ability of thepolymeric network of the coating to associate with a pharmaceuticallyactive agent. The association of the polymeric network of the coatingwith a pharmaceutically active agent may be accomplished by any mode ofmolecular recognition or inclusion including, but not limited to, ionicinteractions, hydrogen bonding and other dipole-dipole interactions,covalent attachment, interpenetration by solvent swelling, metalion-ligand interactions, hydrophilic interactions, hydrophobicinteractions including π-π stacking interactions, or any combinationthereof.

[0050] The terms “pharmaceutically active agent”, “biologically activecompound”, “active agent” and “drug” are used herein interchangeably andinclude pharmacologically active substances that produce a local orsystemic effect in an animal. The terms thus mean any substance intendedfor use in the diagnosis, cure, mitigation, treatment or prevention ofdisease or in the enhancement of desirable physical or mentaldevelopment and conditions in an animal. The term “animal” used hereinis taken to include humans, sheep, horses, cattle, pigs, dogs, cats,rats, mice; birds; reptiles; fish; insects; arachnids; protists (e.g.protozoa); and prokaryotic bacteria.

[0051] The active agents that can be delivered according to the presentinvention include inorganic and organic drugs without limitation andinclude drugs that act on the peripheral nerves, adrenergic receptors,cholinergic receptors, nervous system, skeletal muscles, cardiovascularsystem, smooth muscles, blood circulatory system, synaptic sites,neuro-effector junctional sites, endocrine system, hormone systems,immunological system, reproductive system, skeletal system, autocoidsystems, alimentary and excretory systems, histamine systems, and thelike. The active drug that can be delivered for acting on theserecipients includes, but is not limited to, anticonvulsants, analgesics,antiparkinsons, anti-inflammatories, calcium antagonists, anesthetics,antimicrobials, antimalarials, antiparasitics, antihypertensives,antihistamines, antipyretics, alpha-adrenergic agonists, alpha-blockers,biocides, bactericides, bronchial dilators, beta-adrenergic blockingdrugs, contraceptives, cardiovascular drugs, calcium channel inhibitors,depressants, diagnostics, diuretics, electrolytes, enzymes, hypnotics,hormones, hypoglycemics, hyperglycemics, muscle contractants, musclerelaxants, neoplastics, glycoproteins, nucleoproteins, lipoproteins,ophthalmics, psychic energizers, sedatives, steroids sympathomimetics,parasympathomimetics, tranquilizers, urinary tract drugs, vaccines,vaginal drugs, vitamins, collagen, hyaluronic acid, nonsteroidalanti-inflammatory drugs, angiotensin converting enzymes,polynucleotides, polypeptides, polysaccharides, and the like.

[0052] The present invention is particularly suitable for deliveringpolypeptide drugs which are water soluble. Exemplary drugs include, butare not limited to, insulin; growth factors, such as epidermal growthfactor (EGF), insulin-like growth factor (IGF), transforming growthfactor (TGF), nerve growth factor (NGF), platelet-derived growth factor(PDGF), bone morphogenic protein (BMP), fibroblast growth factor and thelike; somatostatin; somatotropin; somatropin; somatrem; calcitonin;parathyroid hormone; colony stimulating factors (CSF); clotting factors;tumor necrosis factors; interferons; interleukins; gastrointestinalpeptides, such as vasoactive intestinal peptide (VIP), cholecytokinin(CCK), gastrin, secretin, and the like; erythropoietins; growth hormoneand GRF; vasopressins; octreotide; pancreatic enzymes; dismutases suchas superoxide dismutase; thyrotropin releasing hormone (TRH); thyroidstimulating hormone; luteinizing hormone; LHRH; GHRH; tissue plasminogenactivators; macrophage activator; chorionic gonadotropin; heparin;atrial natriuretic peptide; hemoglobin; retroviral vectors; relaxin;cyclosporin; oxytocin; and peptide or polypeptide vaccines. Otherparticularly suitable drugs include polysaccharide including, but notlimited to, hyaluronic acid.

[0053] Preferred drugs include anti-thrombogenics, such as heparin andheparin complexes, enoxaprin, aspirin and hirudin; anti-proliferatives,such as monoclonal antibodies capable of blocking smooth muscle cellproliferation, heparin, angiopeptin and enoxaprin; and antioxidants,such as nitric oxide. Preferred heparin complexes include, but are notlimited to, heparin-tridodecylmethylammonium chloride,heparin-benzalkonium chloride, heparin-steralkonium chloride,heparin-poly-N-vinyl-pyrrolidone, heparin-lecithin,heparin-didodecyldimethylammonium bromide, heparin-pyridinium chloride,and heparin-synthetic glycolipid complex.

[0054] A preferred embodiment of the present invention involvescontacting a medical device having a lubricious, drug-accommodating,coating of the invention with an aqueous solution containing apharmaceutically active agent dissolved or dispersed therein. Ahydrophilic polymer coating, or other cellular polymeric coating, whenexposed to a solution of an active agent, such as an aqueous solution ofheparin, will swell to contain the solution. Upon drying and/or vacuumremoval of the solvent, what is left behind is a coated substratesurface which contains the active agent (e.g., heparin) in an inwardlydecreasing concentration gradient of an interpenetrating polymericnetwork. The resulting coating becomes drug releasing when exposed to,and consequently re-hydrated or at least partially dissolved with,aqueous biological fluids.

[0055] Another preferred embodiment of the present invention is directedto contacting a medical device having a drug-accommodating coating ofthe invention with a pharmaceutically active agent capable of forming acovalent bond with one or more functional groups within the polymericnetwork, such that the pharmaceutically-active agent becomes bound tothe coating. In a most preferred embodiment, the nucleophilic nitrogenatoms of the polyurea network are allowed to react with an organic orinorganic compound to form a covalent bond. The resulting coating-activeagent bond preferably cleaves to release the active agent when used on amedical device in an environment which can cleave the bond. For example,for covalent bonds subject to cleavage by hydrolysis, the coatingbecomes drug-releasing in an aqueous environment. Forenzymatically-cleavable bonds, the coating becomes drug-releasing in thepresence of a suitable enzyme.

[0056] An especially preferred active agent for association or bondingto the drug-accommodating coating of the present invention is nitricoxide (NO). Physical association or bonding of an N₂O₂ or N₂O₂ ⁻functional group to the polymeric network may be achieved by covalentattachment of a nucleophilic moiety of the polymeric coating with N₂O₂.The nucleophilic residue to which the N₂O₂ or N₂O₂ ⁻ group is attachedmay form part of the polymer itself, i.e., part of the polymer backbone,or may be attached as pendant groups on the polymer backbone. The mannerin which the N₂O₂ or N₂O₂ ⁻ functional group is associated, part of, orincorporated with or contained within, i.e., “bound,” to the polymer isinconsequential to the present invention and all means of association,incorporation and bonding are contemplated herein. For example, the N₂O₂or N₂O₂ ⁻ functional groups of the present invention can be coupled toreactive amine groups to form diazeniumdiolates using methods such asthose disclosed in U.S. Pat. Nos. 5,039,705, 5,366,997, and 5,405,919,the entire contents of which are hereby incorporated by reference.

[0057] The NO-releasing N₂O₂ or N₂O₂ ⁻ functional group is preferably anitric oxide/nucleophile adduct, e.g., the reaction product of nitricoxide and a nucleophile. The nucleophilic residue is preferably that ofa primary amine, a secondary amine, a polyamine or derivatives thereof.Most preferably, the nucleophilic adduct is a urea derivative, such asthe polyurea network formed by the reaction of the amine donor with thepolyisocyanate and/or isocyanatosilane of the coating composition.

[0058] The nitric oxide-releasing N₂O₂ or N₂O₂ ⁻ functional groups thatare bound to the polymer generally are capable of releasing nitric oxidein an aqueous environment such as body fluid, i.e., they do not requireactivation through redox or electron transfer. While the polymer-boundNO-releasing coating compositions of the present invention are capableof releasing NO in an aqueous solution, such a composition preferablyreleases NO under physiological conditions.

[0059] After applying the coating solution to a substrate, the solventis preferably allowed to evaporate from the coated substrate, such as byexposure to ambient conditions for at least 5 minutes.

[0060] The coating is subsequently cured. The cure time, temperature,and humidity vary with the choice of solvent, polyisocyanate; polyol andpolyamine; isocyanatosilane adduct; and the composition of thesubstrate. The curing rate may be increased by the addition of smallamounts water to the coating mixture prior to applying the coating tothe substrate.

[0061] Cure temperatures may range from about 75° F. to about 350° F.Cure times may range from about 2 minutes to about 72 hours, dependingupon the solvent, cure temperature and the reactivity of thepolyisocyanate, amine donor, and isocyanatosilane adduct. Preferred cureconditions are about 150° F. to about 220° F. for about 20 minutes toabout 8 hours. In all cases the cure conditions should benon-deleterious to the underlying substrate.

[0062] After the coating is cured, it is preferable to rinse or soak thecoating in water to remove any uncomplexed polymers. Generally, a briefrinse of 10-15 seconds is sufficient, however, a longer rinse or soak isacceptable since the coating is cured and forms a stable gel when incontact with water. After rinsing, the coating may be dried either atambient conditions, or at elevated temperatures or combinations thereofat reduced pressure.

[0063] After the coating is formed, the coating can imbibe water from anaqueous solution prior to introduction to the body and can becomelubricious. Alternatively, the coating can imbibe water solely from bodyfluids, even if not exposed to water prior to introduction into thebody. Because the coating is a cross-linked system, it adheres well tothe substrate even when hydrated. The coating retains its lubricatingproperties even after subsequent drying and rehydration. If the coatingis to be used in a body-related application, such as in catheters,introducer tubes and the like, the materials selected should becompatible with the body and non-toxic to the body. Biocompatiblematerials include, but are not limited to, polyethylene, polypropylene,polyurethane, naturally occurring polymers, stainless steel and otheralloys.

[0064] The coating may be applied to various substrates, including, butnot limited to, metals, ceramics, polymers, and glass.

[0065] The coating may be applied to metal substrates such as thestainless steel used for guide wires, stents, catheters and otherdevices.

[0066] Organic substrates which may be coated with the coatings of thisinvention include, but are not limited to, polyether block amide,polyethylene terephthalate, polyetherurethane, polyesterurethane, otherpolyurethanes, natural rubber, rubber latex, synthetic rubbers,polyester-polyether copolymers, polycarbonates, and other organicmaterials. Some of these materials are available under varioustrademarks such as Pebax™ available from Atochem, Inc. of Glen Rock, N.J.; Mylar™ available from E.I. duPont deNemours and Co. of Wilmington,Del.; Texin™ 985A from Bayer Corporation of Pittsburgh, Pa.; Pellethane™available from Dow Chemical of Midland, Mich.; and Lexan™ available fromGeneral Electric Company of Pittsfield, Mass.

[0067] The polyisocyanate is preferably an aromatic polyisocyanate. Morepreferably, the polyisocyanate is an aromatic polyisocyanate based ontoluene diisocyanate and is dissolved in propylene glycol monomethylacetate and xylene. Preferably, the amount of polyisocyanate ranges fromabout 0.2 to about 10 percent by weight based upon 100% total weight ofcoating mixture. Particularly preferred polyisocyanates includem-xylylene diisocyanate, m-tetramethylxylylene diisocyanate known asmeta-TMXDI available from Cytec Industries, Inc., Stamford, Conn., andthe aromatic polyisocyanate known as Desmodur CB 60N available fromBayer Corporation, Pittsburgh, Pa.

[0068] Examples of suitable amine donors which may be incorporated inthe mixture in addition to or in lieu of a hydroxyl donor include, butare not limited to, C₁-C₁₀ cycloalkyl, alkyl and alkenyl monoamines suchas methylamine, ethylamine, diethylamide, ethylmethylamine,triethylamine, n-propylamine, allylamine, isopropylamine, n-butylamine,n-butylmethylamine, n-amylamine, n-hexylamine, 2-ethylhexylamine,cyclohexylamine, ethylenediamine, polyethyleneamine, 1,4-butanediamine,1,6-hexanediamine, N-methylcyclohexylamine and alkylene amines such asethyleneimine. Preferred amine donors include triethylene glycolaminewhich has the formula H₂NCH₂CH₂OCH₂CH₂OCH₂CH₂NH₂ and an approximatemolecular weight of about 148 available as JeffamineTM XTJ-504 fromHuntsman Corp., Salt Lake City, Utah; polyetherdiamines such asJeffamine™ XTJ-500 and XTJ-501 which have a predominantly polyethyleneoxide backbone and an approximate molecular weight of 600 and 900,respectively, available from Huntsman Corp., Salt Lake City, Utah;polyethertriamines such as Jeffamine™ T-403 which is a polypropyleneoxide-based triamine and has an approximate molecular weight of 440available from Huntsman Corp., Salt Lake City, Utah; and amineterminated polypropyleneglycols such as Jeffamine™ D-400 and Jeffamine™D-2000 which have approximate molecular weights of 400 and 2000,respectively. Other amine donors include urethane modified melaminepolyols containing amine and hydroxyl groups available as Cylink HPC™from Lytec Industries, West Patterson, N.J.

[0069] The hydroxyl donor is preferably a polyol. Polyols useful in thisinvention may be any of a large number of polyols reactive with thepolyisocyanate and isocyanatosilane to form a polyurethane network.Examples of suitable polyols include, but are not limited to, polyesterpolyols, polyether polyols, modified polyether polyols, polyester etherpolyols, castor oil polyols, and polyacrylate polyols, includingDesmophen™ A450, A365, and A160 available from Bayer Corporation,Pittsburgh, Pa. Preferred polyols include castor oil derivatives(triglyceride of 12-hydroxyoleic acid) such as DB oil, Polycin™ 12,Polycin™ 55, and Polycin™ 99F available from CasChem, Inc. of Bayonne,N.J. More preferably, the polyol is polyester based, such as Desmophen™1800. Suitable diols include, but are not limited to, poly(ethyleneadipates), poly(ethyleneglycol adipates), polycaprolactone diols, andpolycaprolactone-polyadipate copolymer diols,poly(ethyleneterephthalate) polyols, polycarbonate diols,polytetramethylene ether glycol, ethyleneoxide adducts of polypropylenetriols. Suitable products include Desmophen™ 651A-65, 1300-75 and 800available from Bayer Corporation of Pittsburgh, Pa., Niax™ E-59 andothers available from Union Carbide of Danbury, Conn., Desmophen™ 550DU,1600U, 1920D, and 1150 available from Bayer Corporation. Many otherpolyols are available and may be used as known to those skilled in theart.

[0070] Coating solutions containing amine donors are typically easier toprocess, quicker to cure, and form more rigid, lower viscosity coatingsthan coating solutions containing hydroxyl donor and no amine donor.Coating solutions containing amine donors, however, typically have ashorter pot life and form less flexible coatings than coating solutionscontaining hydroxyl donors.

[0071] Hydroxyl donors in the coating solution cause the formation ofpolyurethane. In contrast, amine donors in the coating solution causeformation of a polyurea network. A polyurea network may provide betterbiocompatibility and stability than a polyurethane network since chaincleavage does not occur. Further, polyurea networks typically havebetter network properties, such as fatigue resistance, than polyurethanenetworks.

[0072] The amount of hydroxyl and amine donor in the coating mixture maybe varied to obtain desirable surface properties for the coating. Forexample, the amine donor may be varied to obtain a desired lubricity.Preferably, the amount of hydroxyl donor ranges from about 0.2 to about10 percent by weight and the amount of amine donor ranges from about 0.2to about 10 percent by weight based upon 100% total weight of coatingmixture.

[0073] Preferably, the polymer selected from the group consisting ofpolyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol,polyethylene glycol, and polyacrylic acid is polyethylene oxide. More,preferably, the polymer is polyethylene oxide having a molecular weightof about 300,000, such as Polyox™ available from Union Carbide Corp ofSouth Charleston, W.V. The polymer preferably has a mean molecularweight of from about 100,000 to about 2,000,000. Preferably, the amountof the polymer ranges from about 0.2 to about 20 percent by weight basedupon 100% total weight of coating mixture. Reduction of theconcentration of the water soluble polymer in the coating matrix willincrease the amine concentration in the polymer, thereby increasing thenumber of nucleophilic amine sites available for reaction with apharmaceutically-active agent, e.g., by nitrosylation with N₂O₂.

[0074] The isocyanatosilane adduct has one or more unreacted isocyanatefunctional groups. An isocyanatosilane having two or more unreactedisocyanate functional groups may be produced by reacting a silane, suchas aminosilane or mercaptosilane, with polyisocyanate. Theisocyanatosilane has at least one hydrolyzeable alkoxy bonded tosilicon. Preferably, the amount of isocyanatosilane ranges from about0.1 to about 10 percent by weight based upon 100% total weight ofcoating mixture.

[0075] The solvent should not react with the polyisocyanate; aminedonor; hydroxy donor; polymer selected from the group consisting ofpolyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol,polyethylene glycol, and polyacrylic acid; or isocyanatosilane adductbut is a solvent for all the components of the mixture. The solvent ispreferably free of reactive amine, hydroxyl and carboxyl groups.Suitable solvents include, but are not limited to, methylene chloride,tetrahydrofuran (THF), acetonitrile, chloroform, dichloroethane,dichloroethylene, and methylene bromide. Preferably, the solvent isacetonitrile and THF, especially with a ratio of acetonitrile to THF ofabout 3:1.

[0076] Wetting agents may be added to the coating solution to improvewettability to hydrophobic surfaces. Wetting agents include, but are notlimited to, fluorinated alkyl esters, such as Fluorad™ FC-430 availablefrom 3M Corp., and octylphenol ethylene oxide condensates, such asTriton™ X-100 available from Union Carbide. A preferred concentration ofwetting agent in the coating solution is from about 0.01 to about 0.2%by weight based upon 100% solids in the coating solution.

[0077] Viscosity and flow control agents may be added to the coatingmixture to adjust the viscosity and thixotropy of the mixture to adesired level. Preferably, the viscosity is such that the coating may beformed on the substrate at the desired thickness. Viscosities of fromabout 50 cps to about 500 cps may be used although higher or lowerviscosities may be useful in certain instances. Viscosity control agentsinclude, but are not limited to, fumed silica, cellulose acetatebutyrate, and ethyl acrylate/2-ethyl hexyl acrylate copolymer. Flowcontrol agents are preferably present in amounts of from about 0.05 toabout 5 percent by weight based upon 100% total weight of coatingmixture.

[0078] Antioxidants may be added to the coating mixture to improveoxidative stability of the cured coatings. Antioxidants include, but arenot limited to, tris(3,5-di-t-butyl-4-hydroxybenzyl)isocyanurate,2,2′-methylenebis(4-methyl-6-t-butylphenol),1,3,5-trimethyl-2,4,6-tris(3,5-di-t-butyl-4-hydroxybenzyl)benzene,butylhydroxytoluene, octadecyl 3,5-di-t-butyl-4-hydroxyhydrocinnamate,4,4 methylenebis(2,6-di-butylphenol), p,p′-dioctyl diphenylamine, and1,1,3-tris-(2-methyl-4-hydroxy-5-t-butylphenyl)butane. Antioxidants arepreferably present in amounts from 0.01 to 1 percent by weight basedupon 100% total weight of coating mixture.

[0079] Conventional pigments may be added to the coating mixture toimpart color or radiopacity, or to improve the appearance of thecoatings.

[0080] Air release agents or defoamers which are optionally included inthe coating solution include, but are not limited to, polydimethylsiloxanes, 2,4,7,9-tetramethyl-5-decyn-4,7-diol, 2-ethylhexyl alcohol,and n-beta-aminoethyl-gamma-amino-propyl-trimethoxysilane. Air releaseagents are preferably added in amounts from 0.005 to 0.5 percent byweight based upon 100% total weight of coating mixture.

[0081] Methods of Use

[0082] The present invention provides a method of regulating ormodulating a local or systemic biological process or state involvingnitric oxide by contacting the tissue of a patient in need thereof witha medical device having a lubricious, nitric oxide-releasing coating ofthe invention. These biological processes include, but are not limitedto, control of blood pressure, macrophage-induced cytostasis andcytotoxicity, neurotransmission, smooth muscle cell proliferation,pulmonary tone, pulmonary and systemic circulation, regulation ofamniotic fluid, stimulation of learning processes, mediation of sensoryinhibition, cerebrovascular tone, chest tube drainage, and arterialoxygenation.

[0083] In one embodiment, a medical device coated with a lubricious,nitric oxide-releasing coating of the invention is used in a method ofreducing restenosis or treating or preventing complications associatedwith restenosis. Persons in need of such treatment and/or preventioninclude those who have undergone or are undergoing angioplasty, or haveexperienced a vascular injury. The use of a medical device with alubricious, nitric-oxide-releasing coating of the invention need notnecessarily completely ameliorate restenosis. Further such use can be inconjunction with other treatments for restenosis known to those of skillin the art.

[0084] In another embodiment, a medical device coated with a lubricious,nitric-oxide coating of the invention is provided as a “preventive”treatment before detection of restenosis, so as to prevent the same fromdeveloping in patients at high risk for the same, such as, for example,angioplasty patients. In particular, a coated medical device of thepresent invention is used in a method of preventing or reducingrestenosis associated with a percutaneous procedure or surgical therapyselected from coronary artery bypass graft surgery (CABG), percutaneoustranslumenal coronary angioplasty (PTCA), directional atherectomy, andheart transplantation.

[0085] In another embodiment, a medical device coated with a lubricious,nitric-oxide-releasing coating of the invention is employed in a methodof mediating the induction of angiogenesis. Such a method is useful forinducing new blood vessel development and increasing blood flow in areaswith limited blood flow, and particularly useful in patients diagnosedwith ischemia. In a preferred embodiment, a device coated with alubricious, nitric-oxide-releasing coating of the invention is used incombination with transmyocardial laser revascularization to stimulateangiogenesis.

[0086] In another embodiment, the present invention is directed to therelease of nitric oxide from a medical device coated with a lubricious,nitric-oxide-releasing coating of the invention in a patient that hasbeen diagnosed with a disease or condition which is responsive to NOadministration. Diseases or conditions that are treatable according tothe present invention include abnormal blood pressure, restenosis,thrombosis, atherosclerosis, hypertension, myocardial ischemic, angina,intimal hyperplasia, benign prostatic hyperplasia, hypoxemia associatedwith Eisenmenger syndrome, ventilation/perfusion mismatch, acuterespiratory distress syndrome, pulmonary infection, acute chest syndromeof sickle cell disease, Raynard's phenomenon in scleroderma patients,and bronchoconstriction.

[0087] The patients referred to herein are preferably mammals, and mostpreferably humans.

[0088] Animal Models

[0089] In-Stent Restenosis:

[0090] The porcine stent injury model (Kornowski et al., J. Am. Coll.Cardiol. 31:224-230 (1998)) mimics restenosis due to intimalhyperplasia. Coronary vessels are imaged by angiography, injured byinflation of an over-sized balloon catheter, and stents are placed inthe injured region by balloon deployment. After 28 days, repeatangiographic images are obtained, the animal is sacrificed and vesselsare recovered for determination of restenosis by histomorphometricmeasures (lumen area, neo-intimal thickness, and % area stenosis).Arterial injury at each stent strut is also quantified for correlationwith outcome.

[0091] Angiogenesis Induction:

[0092] The ischemic pig myocardium model and other alternative models ofinduced, although not therapeutic, angiogenesis are available and can beused to evaluate NO-generating implant materials. The murineangiogenesis model (Passaniti, A., Lab Invest 67:804 (1992); Montrucchioet al., Am. J. Pathol. 151:557 (1997)) has the advantage of requiringonly small samples of materials and providing results within less thanone week. In this model, test materials are imbedded in Matrigel, placedin the abdominal wall of mice, and angiogenesis is measured by a bloodvessel count in histological sections taken 2-5 days post-implantation.

[0093] A pig model of induced angiogenesis can be used for evaluation ofNO generating full size myoimplant devices in the appropriate tissuesite. In this model four/six metallic implants are placed in the leftventricular wall using a specially designed delivery device. Ascontrols, one hole is cored with a biopsy punch and one additional holeis poked with a needle. During implant placement (or control holecreation), the following measurements are made: systemic blood pressurepre- and post-implant (or control hole); continuous ECG; LV functionpre- and post-implant (or control hole); fluoroscopy as needed; andobserve time for bleeding to stop, post-implant.

[0094] The entire experiment is performed with attention to sterileprocedure. After placement of the implants and control holes, theanimals are closed, kept alive and blood pressure monitored daily in thefirst post-operative week.

[0095] Upon sacrifice, the hearts are rapidly harvested, perfusion fixedand placed in cold formalin. Coded specimens are photographed, openedalong the interventricular septum, X-rayed and implants removed. Tissuesurrounding implants from the epicardial and endocardial surface controlholes and corresponding untreated areas is embedded in parraffin. LMsection (5 microns) are stained with H&E, Masson's trichrome andendothelial cell markers (e.g. anti-vonWillebrand factor and anti-TEK)using standard immunohistochemical techniques.

[0096] Slides are evaluated for inflammation (scale of 0-4) and vasculardensity (number of antibody positive structures with at least one layerof smooth muscle cell/cm²) by a blinded pathologist. Vascular densityfor the implant regions is compared to the corresponding non-implantregions using a paired student's t-test. Statistical significance isconsidered a p value <0.05.

[0097] Preferably, a successful NO-generating implant will increasevascular density 2-fold compared with the untreated myoimplant. If theNO-generating implant successfully induces angiogenesis in the normalpig myocardium, myoimplants will be tested in a porcine model ofischemic heart disease. This protocol is similar to that described (St.Louis et al., J. Am. Coll. Cardiol. 31(supp. A):490A (1998)), and is runas outlined below using the same experimental design as for inducedangiogenesis in the porcine model.

[0098] Chronic Ischemic Pig Model:

[0099] Mini-swine undergo subtotal left circumflex (LCX) coronaryocclusion to reduce resting blood flow to 10% of baseline as assessedusing an implanted flow probe (St. Louis et al., J. Am. Coll. Cardiol.31(supp. A):490A (1998)). After two weeks in the low-flow state,dubotamine stress echocardiography (DSE) and positron emissiontomography (PET) are performed to document ischemic (hibernating)myocardium in the LCX distribution. After verifying ischemia, animalsare prepared for myocardial device implants.

[0100] PET scans are interpreted as showing ischemic, viable myocardiumif a flow deficit is noted in the lateral and posterioinferior walls ofthe left ventricle supplied by the LCX accompanied by normal orincreased glucose utilization in these same regions. Using DSE,viability in the lateral and posterinferior walls of the left ventricleis defined as an improvement in systolic wall thickening with low dosedobutamine in myocardial regions with severe hypocontractility at rest.Viable segments are considered iscehmic if systolic wall motiondeteriorates with stress.

[0101] The specific variables to be compared are: changes in perfusionby PET 3 months post-implant; changes in wall motion score by DSE 3months post-implant; time to improvement in wall motion scores by DSE,specifically, performing serial echoes at 1, 2 and 3 months; andvascular density analysis to confirm the presence of endothelial cellswithin putative neovessels at 3 months.

[0102] NO-generating stents are tested according to a modified methoddescribed by Kornowski et al., J. Am. Coll. Cardiol. 31:224-230 (1998),and outlined below.

[0103] Porcine Stent Injury Model:

[0104] In the porcine stent injury model, pathogen-free domestic pigsare pretreated with aspirin/ticlopidine and slow release verapamil oneday before stent placement. Following anesthesia and intubation, heparinis administered I.V. and control angiograms of the left coronaryarteries are performed. Before stent implantation, all animals undergoballoon injury for one minute (at 1.2:1 balloon/artery ratio) in theleft anterior descending (LAD) and left circumflex (LCX). One stent isballoon-deployed at both sites. Repeat angiograms are obtainedimmediately after stent implantation. All equipment is removed and theanimal is revived and maintained for 28 days under predeterminedconditions. Animals undergo repeat angiography in the same orthogonalviews before death and perfusion fixed hearts are harvested forhistology.

[0105] The following Quantitative Coronary Angiographic (QCA)Measurements are made preand post-stent implantation and at sacrifice:mean artery reference diameter (proximal and distal); mean stentdiameter at full expansion; minimal stent diameter at follow-up; %diameter stenosis at follow-up (mean stent diameter−minimal stentdiameter/mean stent diameter×100).

[0106] Histomorphometric Analysis:

[0107] Formalin-fixed specimens are embedded in methacrylate and 50-100micron sections are obtained at about 1 mm intervals and stained withmethylchromatin. Measurements are made on four cross sections from eachstent corresponding to the minimal lumen diameter (by QCA) and averagedfor each stent: lumen area; neo-intimal thickness; and neo-intimal %area stenosis (1-[stenotic lumen area/original lumen area]×100).

[0108] Arterial injury at each stent strut is determined by the anatomicstructures penetrated by each strut. Injury score is assigned as: 0, noinjury; 1, internal elastic lamina tear; 2, medial tear; and 3, externalelastic lamina laceration. The average score for each segment iscalculated by dividing the sum of scores by the total number of strutsin the examined section.

[0109] Dosage/Loading

[0110] Defining the loading characteristics of NO-generating moleculesonto materials used to create implants and determining the releasekinetics under physiological conditions will open the way for thedevelopment of many additional types of implant devices. Systemicadministration of NO may lead to undesirable side effects because of thelarge number of processes which are affected by this very powerfulbiological effector. Local delivery of the molecule from implanteddevices represents a very effective way to control both the dose andlocalization of NO. Accordingly, the determination of the optimalmethods for loading NO-generating molecules onto materials suitable forimplant construction and the kinetics of release of NO from fully loadedimplant materials in buffers and under physiological conditions is anaspect of the present invention.

[0111] Loading dosages and release profiles of nitric oxide from amedical device coated with a lubricious, nitric oxide-releasing coatingof the invention can be determined readily by those with ordinary skillin the art. Generally, the loading dosage and desired release profilewill vary depending upon considerations such as: age; health; medicalcondition being treated; kind of concurrent treatment, if any; nature ofthe effect desired; extent of tissue damage; gender; duration ofsymptoms; and counter indications, if any, and other variables to beadjusted by the individual physician.

[0112] An aspect of the present invention is the determination of themaximum amount of each NO-generating molecule which can be loaded ontoeach type of implant material and the determination of the kinetics ofrelease of NO. As described above, the NO-releasing materials arequantitatively tested for thrombogenicity, an undesirablecharacteristic, as well as classified as to their cytostatic andangiogenic properties.

[0113] The following non-limiting example is meant to be an illustrativeembodiment of a lubricious, nitric-oxide releasing coating of thepresent invention.

EXAMPLE 1

[0114] A coating solution was prepared by combining the followingingredients and mixing them thoroughly:

[0115] (a) 0.32 g. of an aromatic polyisocyanate adduct based on toluenediisocyanate and dissolved in propylene glycol monomethyl acetate andxylene having an NCO content of about 10.5% and a molecular weight ofabout 400 available as Desmodur™ CB 60 from Bayer Corporation;

[0116] (b) 0.67 g. of a solvent-free, saturated polyester resin (polyol)available as Desmophen™ 1800 from Bayer Corporation;

[0117] (c) 0.91 g. of polyethylene oxide available as Polyox™ having amolecular weight of about 300,000 from Union Carbide Corp.,

[0118] (d) 76.97 g. acetonitrile;

[0119] (e) 21.82 g. THF; and

[0120] (f) 2.02 g. 3-isocyanyopropyltriethoxysilane available as UCT17840-KG from United Chemical Technologies, Bristol, Pa.

[0121] Five 18″ inch wires were coated with the solution by dipping for11 seconds. The solvent was evaporated at ambient conditions forapproximately 20 minutes. The wires were then placed in an oven at 40°C. for 10 hours to cure the coating.

[0122] Upon removal from the oven, the wires were rinsed in water anddried.

[0123] The coating was tested by ASTM D 1894-87 Standard Test Methodsfor Static and Kinetic Coefficients of Friction of Plastic Film andSheeting.

[0124] Having now fully described this invention, it will be understoodto those of ordinary skill in the art that the same can be performedwithin a wide and equivalent range of conditions, formulations, andother parameters without affecting the scope of the invention or anyembodiment thereof. All patents and publications cited herein are fullyincorporated by reference in their entirety.

What is claimed is:
 1. A method of preventing or inhibiting restenosisin a patient in need thereof, comprising implanting an NO-releasingmedical device into said patient, said medical device having a coatingof: nitric oxide associated with and releasable from a polyurea networkformed from reaction on said medical device of a mixture comprising: (a)a polyisocyanate; (b) an amine donor; (c) an isocyanatosilane adducthaving at least one terminal isocyanate group and at least onehydrolyzable alkoxy group bonded to silicon; and optionally (d) apolymer selected from the group consisting of a polyethylene oxide,polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, andpolyacrylic acid.
 2. A method of restoring vascular function in apatient in need thereof, comprising implanting an NO-releasing medicaldevice into said patient, said medical device having a coating of:nitric oxide associated with and releasable from a polyurea networkformed from reaction on said medical device of a mixture comprising: (a)a polyisocyanate; (b) an amine donor; (c) an isocyanatosilane adducthaving at least one terminal isocyanate group and at least onehydrolyzable alkoxy group bonded to silicon; and optionally (d) apolymer selected from the group consisting of a polyethylene oxide,polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, andpolyacrylic acid.
 3. A method of preventing or inhibiting coronaryartery disease, cardiac ischemia, or congestive heart failure in apatient, comprising implanting an NO-releasing medical device into saidpatient, said medical device having a coating of: nitric oxideassociated with and releasable from a polyurea network formed fromreaction on said medical device of a mixture comprising: (a) apolyisocyanate; (b) an amine donor; (c) an isocyanatosilane adducthaving at least one terminal isocyanate group and at least onehydrolyzable alkoxy group bonded to silicon; and optionally (d) apolymer selected from the group consisting of a polyethylene oxide,polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, andpolyacrylic acid.
 4. A method of administering NO to the vascular tissueof a human, comprising contacting said vascular tissue with a medicaldevice having a coating of: nitric oxide associated with and releasablefrom a polyurea network formed from reaction on said medical device of amixture comprising: (a) a polyisocyanate; (b) an amine donor; (c) anisocyanatosilane adduct having at least one terminal isocyanate groupand at least one hydrolyzable alkoxy group bonded to silicon; andoptionally (d) a polymer selected from the group consisting of apolyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol,polyethylene glycol, and polyacrylic acid.
 5. The method according toclaim 4, wherein said nitric oxide is associated with said polyureanetwork as a functional group selected from N₂O₂ or N₂O₂ ⁻.
 6. Themethod according to claim 4, wherein said nitric oxide-releasingfunctional group is covalently attached to said polyurea network.
 7. Themethod according to claim 6, wherein said nitric oxide-releasingfunctional group is covalently attached to a nitrogen atom.
 8. Themethod according to claim 7, wherein said covalent bond comprises X—N₂O₂or X—N₂O₂ ⁻, wherein X is a primary amine, a secondary amine, apolyamine or a derivative thereof.
 9. A method of restoring normallevels of NO to the vascular tissue of a human following a procedureselected from the group consisting of balloon angioplasty, PCTA(percutaneous translumenal coronary angioplasty) and CABG (coronaryartery bypass graft), comprising inserting a medical device into saidhuman during said procedure, said medical device having a coating of:nitric oxide associated with and releasable from a polyurea networkformed from reaction on said medical device of a mixture comprising: (a)a polyisocyanate; (b) an amine donor; (c) an isocyanatosilane adducthaving at least one terminal isocyanate group and at least onehydrolyzable alkoxy group bonded to silicon; and optionally (d) apolymer selected from the group consisting of a polyethylene oxide,polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, andpolyacrylic acid.
 10. A method of treating a human with a conditionselected from the group consisting of hypertension, atherosclerosis,restenosis, tissue ischemia, coronary artery disease, cardiac ischemia,congestive heart failure and refractory coronary ischemic syndrome,comprising inserting an NO-releasing medical device into said human,said medical device having a coating of: nitric oxide associated withand releasable from a polyurea network formed from reaction on saidmedical device of a mixture comprising: (a) a polyisocyanate; (b) anamine donor; (c) an isocyanatosilane adduct having at least one terminalisocyanate group and at least one hydrolyzable alkoxy group bonded tosilicon; and optionally (d) a polymer selected from the group consistingof a polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol,polyethylene glycol, and polyacrylic acid.
 11. A method of mediating theinduction of angiogenesis in a patient in need thereof, comprisinginserting an NO-releasing medical device into said human, said medicaldevice having a coating of: nitric oxide associated with and releasablefrom a polyurea network formed from reaction on said medical device of amixture comprising: (a) a polyisocyanate; (b) an amine donor; (c) anisocyanatosilane adduct having at least one terminal isocyanate groupand at least one hydrolyzable alkoxy group bonded to silicon; andoptionally (d) a polymer selected from the group consisting of apolyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol,polyethylene glycol, and polyacrylic acid.
 12. A method according toclaim 11, wherein said patient has been diagnosed with ischemia.
 13. Amethod according to claim 11, wherein said medical device is insertedinto said patient as part of a transmyocardial laser revascularizationprocedure.
 14. A method of administering nitric oxide to a patientdiagnosed with a disease or condition responsive to nitric oxideadministration, comprising inserting an NO-releasing medical device intosaid patient, said medical device having a coating of: nitric oxideassociated with and releasable from a polyurea network formed fromreaction on said medical device of a mixture comprising: (a) apolyisocyanate; (b) an amine donor; (c) an isocyanatosilane adducthaving at least one terminal isocyanate group and at least onehydrolyzable alkoxy group bonded to silicon; and optionally (d) apolymer selected from the group consisting of a polyethylene oxide,polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, andpolyacrylic acid.
 15. A method according to claim 14, wherein saiddisease or condition is selected from restenosis, thrombosis,atherosclerosis, hypertension, myocardial ischemia, angina, intimalhyperplasia, benign prostatic hyperplasia, hypoxemia associated withEisenmenger syndrome, ventilation/perfusion mismatch, acute respiratorydistress syndrome, pulmonary infection, acute chest syndrome of sicklecell disease, Raynard's phenomenon in scleroderma, andbronchoconstriction.